Tofacitinib inhibits granulocyte-macrophage colony-stimulating factor-induced NLRP3 inflammasome activation in human neutrophils

Arthritis Research & Therapy
Makiko Yashiro FuruyaKiyoshi Migita

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has emerged as a crucial cytokine that activates myeloid cells to initiate tissue inflammation. However, the molecular actions of GM-CSF against innate immunity are still poorly characterized. Here, we investigated the in vitro effects of GM-CSF on the activation of human myeloid lineages, neutrophils, and the underlying intracellular signaling mechanism, including inflammasome activation. Human neutrophils were stimulated with GM-CSF in the presence or absence of tofacitinib. The cellular supernatants were analyzed for interleukin-1 beta (IL-1β) and caspase-1 by enzyme-linked immunosorbent assay (ELISA) methods. Pro-IL-1β mRNA expressions in human neutrophils were analyzed by real-time polymerase chain reaction. Protein phosphorylation of neutrophils was assessed by Western blot using phospho-specific antibodies. Stimulation with GM-CSF alone, but not tumor necrosis factor-alpha, was shown to increase the release of IL-1β and cleaved caspase-1 (p20) from human neutrophils. Tofacitinib, which inhibits GM-CSF-induced Janus kinase 2 (Jak2)-mediated signal transduction, completely abrogated GM-CSF-induced IL-1β and caspase-1 (p20) secretion from neutrophils. GM-CSF stimulat...Continue Reading

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Citations

Aug 11, 2020·British Journal of Pharmacology·Ilaria BertocchiMassimo Collino
Jun 17, 2020·BMC Immunology·Yuya FujitaKiyoshi Migita
Jan 9, 2021·Naunyn-Schmiedeberg's Archives of Pharmacology·Mohammad BahadoramMohammad-Reza Mahmoudian-Sani
Mar 28, 2021·American Journal of Reproductive Immunology : AJRI·Christopher NoldAnthony T Vella
Feb 23, 2020·Annals of the Rheumatic Diseases·Qiongyi HuChengde Yang
Aug 16, 2021·Arthritis Research & Therapy·Paola Di BenedettoRoberto Giacomelli

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Methods Mentioned

BETA
enzyme-linked immunosorbent assay
ELISA
enzymatic assay

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